Variant rs587776542 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_198586.3(NHLRC1):c.468_469delAG(p.Gly158fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NHLRC1
NM_198586.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 0.707

Variant links:

Genes affected

NHLRC1 (HGNC:21576): (NHL repeat containing E3 ubiquitin protein ligase 1) The protein encoded by this gene is a single subunit E3 ubiquitin ligase. Laforin is polyubiquitinated by the encoded protein. Defects in this intronless gene lead to an accumulation of laforin and onset of Lafora disease, also known as progressive myoclonic epilepsy type 2 (EPM2).[provided by RefSeq, Mar 2010]

NHLRC1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-18122137-CCT-C is Pathogenic according to our data. Variant chr6-18122137-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-18122137-CCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHLRC1	NM_198586.3 linkuse as main transcript	c.468_469delAG	p.Gly158fs	frameshift_variant	1/1	ENST00000340650.6	NP_940988.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHLRC1	ENST00000340650.6 linkuse as main transcript	c.468_469delAG	p.Gly158fs	frameshift_variant	1/1	6	NM_198586.3	ENSP00000345464.3		Q6VVB1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249768

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461664

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lafora disease

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The NHLRC1 c.468_469delAG (p.Gly158ArgfsTer17) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant is reported as the second most common pathogenic variant in the NHLRC1 gene and the most common deletion (Jansen et al. 2007). This variant has been reported in at least four studies and is found in a total of 21 patients with Lafora type progressive myoclonus epilepsy, including 16 in a homozygous state and five in a compound heterozygous state (Chan et al. 2003; Turnbull et al. 2008; Singh et al. 2008; Lesca et al. 2010). Turnbull et al. (2008) demonstrated a founder effect for the variant in the remote tribal villages of Oman. The p.Gly158ArgfsTer17 variant was absent from 280 controls. It is reported at a frequency of 0.00010 in the African population of the Exome Aggregation Consortium but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Gly158ArgfsTer17 variant is classified as pathogenic for Lafora type of progressive myoclonus epilepsy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 22, 2023	This sequence change creates a premature translational stop signal (p.Gly158Argfs*17) in the NHLRC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 238 amino acid(s) of the NHLRC1 protein. This variant is present in population databases (rs587776542, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lafora disease (PMID: 12958597, 18263761, 18311786, 20738377, 28556688). ClinVar contains an entry for this variant (Variation ID: 2588). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

The c.468_469delAG variant, located in coding exon 1 of the NHLRC1 gene, results from a deletion of two nucleotides at nucleotide positions 468 to 469, causing a translational frameshift with a predicted alternate stop codon (p.G158Rfs*17). This mutation is one of the most commonly reported NHLRC1 mutations and has been detected in several individuals with biopsy confirmed Lafora disease in both the homozygous and compound heterozygous states (Singh S et al. Hum. Mutat., 2008 Jun;29:E1-12; Chan EM et al. Nat. Genet., 2003 Oct;35:125-7; Kecmanovi M et al. Clin. Genet., 2016 Jan;89:104-8; Lesca G et al. Epilepsia, 2010 Sep;51:1691-8). In addition to the clinical data presented in the lieterature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Myoclonic epilepsy of Lafora 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 14, 2015

c.468_469delAG: p.Gly158ArgfsX17 (G158RfsX17) in exon 1 of the NHLRC1 gene (NM_198586.2). The normal sequence with the bases that are deleted in braces is: ACTC{AG}GGGGA. The c.468_469delAG mutation in the NHLRC1 gene has been reported previously in association with Lafora disease in individuals who had a second NHLRC1 mutation on the opposite allele (Chan et al., 2003; Singh et al., 2008, Turnbull et al., 2008). The deletion causes a frameshift starting with codon Glycine 158, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Gly158ArgfsX17. This mutation is predicted to cause loss of normal protein function through protein truncation, as the last 238 amino acids of the NHLRC1 protein are lost and replaced with 16 incorrect amino acids. Therefore, c.468_469delAG is considered a disease-causing mutation. The variant is found in EPILEPSYV2-1 panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over